The present invention is generally in the field of enhancing an immune response, and particularly relates to the removal of inhibitors of immune mediators, in combination with anti-angiogenic compounds, cytokines, compounds inducing a procoagulant state, chemotherapeutics and/or radiation.
Conventional cancer therapy is based on the use of drugs and/or radiation which kills replicating cells, hopefully faster than the agents kill the patient""s normal cells. Surgery is used to reduce tumor bulk, but has little impact once the cancer has metatasized. Radiation is effective only in a localized area.
The treatments can in themselves kill the patient, in the absence of maintenance therapy. For example, for some types of cancer, bone marrow transplants have been used to maintain the patient following treatment with otherwise fatal amounts of chemotherapy. Efficacy has not been proven for treatment of solid tumors, however. xe2x80x9cCocktailsxe2x80x9d of different chemotherapeutic agents and combinations of very high doses of chemotherapy with restorative agents, for example, granulocyte macrophage colony stimulating factor (xe2x80x9cGM-CSFxe2x80x9d), erythropoietin, thrombopoetin granulocyte stimulating factor, (xe2x80x9cG-CSFxe2x80x9d), macrophage colony stimulating factor (xe2x80x9cM-CSFxe2x80x9d) and stem cell factor (xe2x80x9cSCFxe2x80x9d) to restore platelet and white cell levels, have been used to treat aggressive cancers. Even with the supportive or restrictive therapy, side effects are severe.
Other treatments have been tried in an attempt to improve mortality and morbidity. Vaccines to stimulate the patient""s immune system have been attempted, but not with great success. Various cytokines, alone or in combination, such as tumor necrosis factor, interferon gamma, and interleukin-2 (xe2x80x9cIL-2xe2x80x9d) have been used to kill cancers, but have not produced cures. More recently, anti-angiogenic compounds such as thalidomide have been tried in compassionate use cases and shown to cause tumor remission. In animal studies, compounds inducing a procoagulant state, such as an inhibitor of protein C, have been used to cause tumor remission. New studies have shown that inhibitors of cytokine receptors, such as tumor necrosis factor receptors (xe2x80x9cTNF-Rsxe2x80x9d) which are released in a soluble form from tumor cells, in high concentrations relative to normal cells, may restore the immune system""s attack on the tumor cells (Jablonska and Peitruska, Arch. Immunol. Ther. Exp. (Warsz) 1997, 45(5-6), 449-453; Chen, et al., J. Neuropathol. Exp. Neurol. 1997, 56(5), 541-550).
U.S. Pat. No. 4,708,713 to Lentz describes an alternative method for treating cancer, involving ultrapheresis to remove compounds based on molecular weight, which promotes an immune attack on the tumors by the patient""s own white cells.
Despite all of these efforts, many patients die from cancer; others are terribly mutilated. It is unlikely that any one therapy will be effective to cure all types of cancer.
It is therefore an object of the present invention to provide a method and compositions for treatment of solid tumors.
It is a further object of the present invention to provide a method and compositions that does not involve non-selective, extremely toxic, systemic chemotherapy.
A method to treat cancer uses ultrapheresis, refined to remove compounds of less than 120,000 daltons molecular weight, followed by administration of replacement fluid, to stimulate the patient""s immune system to attack solid tumors. In the preferred embodiment, the patient is ultrapheresed using a capillary tube ultrafilter or parallel plate filter having a molecular weight cutoff of 120,000 daltons, sufficient to filter at least one blood volume. The preferred replacement fluid is ultrapheresed normal plasma. The patient is preferably treated daily for three weeks, diagnostic tests conducted to verify that there has been shrinkage of the tumors, then the treatment regime is repeated.
The treatment is preferably combined with an alternative therapy, for example, treatment with an anti-angiogenic compound, one or more cytokines such as TNF, gamma interferon, other interferons, or IL-2, or a procoagulant compound. The treatment increases the inflammation against tumors by allowing cytokines, such as TNF, to work effectively. This provides a basis for an improved effect when combined with any treatment that enhances cytokine activity against the tumors, for example, treatments using alkylating agents, doxyrubicin, carboplatinum, cisplatinum, and taxol, and other drugs which may be synergistic in effect with xe2x80x9cunblockedxe2x80x9d cytokines. Alternatively, the ultrapheresis treatment can be combined with local chemotherapy, systemic chemotherapy, and/or radiation.